Description: Intracellular organisms manipulate their host cells to suit their intracellular life styles. These pathogens alter cellular processes by introducing bacterial factors into the host cell. Anaplasma phagocytophilum, which[unreadable] causes Human Granulocytic Ehrlichiosis, is a unique intracellular organism because it is the only human[unreadable] pathogen that specifically survives and multiplies in neutrophils. Neutrophils play an essential role in the[unreadable] immune system and kill bacteria very efficiently. A. phagocytophilum is the exception as it escapes killing[unreadable] by neutrophils. It is poorly understood how A. phagocytophilum manipulates the cellular processes in the[unreadable] neutrophil for its survival. [unreadable] [unreadable] The global hypothesis is that A. phagocytophilum manipulates cellular processes by translocating bacterial factors into the neutrophil ensuring its survival. We have identified a candidate bacterial factor, AnkA, which may mediate these effects. Consequently, A. phagocytophilum infection of neutrophils provides an ideal[unreadable] model to study the pathways involved in neutrophil biology and bacterial killing.[unreadable] [unreadable] Aim 1 examines the tyrosine phosphorylation of AnkA, which allows it to interact with specific host cells[unreadable] proteins through SH2 domains.[unreadable] Aim 2 seeks to identify these host cell proteins and the signaling pathways manipulated by AnkA.[unreadable] Aim 3 examines the effect of AnkA on the respiratory burst, the major killing pathway of the neutrophil.[unreadable] [unreadable] The long-term goals are: 1) the identification of the mechanism leading to survival of A. phagocytophilum in[unreadable] neutrophils, 2) the development new avenues to manipulate neutrophils, leading to potential new[unreadable] treatments of inflammation or infections, and 3) enhancement of our understanding of neutrophil biology as[unreadable] it relates to the immune system.[unreadable] [unreadable] In the Unites States, Human Granulocytic Ehrlichiosis is an emerging tick-associated disease and in[unreadable] endemic areas the incidence is second only to Lyme disease.